Peroxisome proliferator activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and function as transcription factors regulating gene expression in a form of heterodimers with retinoid X receptors (RXRs). The PPARs are divided into three subtypes, “PPARα”, “PPARγ” and “PPARδ”, and are generally involved in maintaining energy homeostasis in vertebrates through the control of fat and glucose metabolisms.
Accordingly, many attempts have been made to develop PPARα and PPARγ full agonists which are useful for the treatment and prevention of disorders modulated by PPARs, e.g., metabolic syndromes such as diabetes, obesity, arteriosclerosis, hyperlipidemia, hyperinsulinism and hypertension; inflammatory diseases such as osteoporosis, liver cirrhosis and asthma; and cancer.
For example, it has been reported that thiazolidine-2,4-dione (TZD) and non-TZD-based full agonists on PPARγ exhibit excellent blood glucose level-lowering effect in non-insulin dependent diabetes mellitus (NIDDM) mammal models (J. Med. Chem., 1999, 42, 3785; Bioorg. Med. Chem. Lett., 2000, 2453; Chem. Pharm. Bull., 2002, 50, 1349; Bio. Med. Chem. Lett., 2002, 77; J. Med. Chem., 2003, 46, 3581).
However, such a PPARγ full agonist is also known to cause adverse side effects including weight gain due to facilitation of fat cell differentiation, cardiac hypertrophy, edema and liver damage.
Therefore, there exists a need to develop selective PPAR modulators (SPPARMs) which are capable of selectively controlling activities of the PPARs without causing side effects (Molecular Cell, 2001, 8, 737; Molecular Endocrinology, 2003, 17, 662; Molecular Endocrinology, 2002, 16, 2628).